mmg_233_2013_genetics_genomicswikiaorg-20200214-history
Heart Rate
Introduction Humans have an average resting heart beat between 60-90 beat per minute where anything below 60 being is often associated with peak cardiovascular fitness and above 90 suggest an increased risk of health related issues. In his physical prime disgraced athlete Lance Armstrong had a resting heart rate of 32 BPM (Increase 2011). The rate of the heart's contractions is controlled by pacemaker cells. Electrical signals are taken in by the SA node, they travel through gap junctions to the AV node, they are then moved by the Bundle of His through the intermuscluar system where they eventually end up at the pukinjie fibers. It is here the ventricles of the heart contract and blood is forced out either as deoxygenated blood to the lungs or oxygenated blood out of the aorta to the rest of the body. Persistent alterations in the rate these signals are recived and moved throughout the heart can lead to serious health problems. Increased heart rate has been shown to increase cardiovascular risk through several mechanisms including myocardial oxygen requirement in which there is a shift in control from the parasympathetic to the sympathetic nervous system. Experimental alteration of the SA node has been shown to influence the progression of atherosclerosis from high cholesterol. Furthermore, human trials for selective heart rate reduction were shown to reduce clinical events in people with heart failure. Experiments dealing with Drosophilia melanogaster ''and ''Danio rerio have identified 20 genes at 11 loci that are related to heart rate regulation. The related genes are related to signal transmission, embryonic cardiac development and the pathophysiology of dialated cardiomyopathy, congenital heart failure and or cardiac death (Identification 2012). Stage 1: GWAS Study to find loci associated with heart rate A meta-analysis was conducted using 2,516,789 SNPs of the human genome and 85,787 persons of European ancestry from 36 GWAS to find the associations between these SNPs and heart rate. The study found 12 loci that has some correlation with heart rate ( 7 previously known loci MYH6, CD46, FADS1, GJA1, ACHE, SLC35F1 and LINC00477 and 5 new loci). The study then continued to analyze 27 more GWAS containing data from 88,823 individuals. The results of this stage supported the findings of the 12 loci found initially, and also added another 9 loci to the mix. Therefore, as a result of this meta-analysis 7 robust loci were supported and 14 new loci were found. Increasing Alleles on Heart Rate A cross analysis was preformed using the 21 loci to determine the effects of the summation of SNPs. The figure to the right compares heart rate to a genetic predisposition score using a histogram shoing the number of people in each category. Further analysis was done using EKGs looking for a correlation between the 21 SNP mutations and atrial fibrillation, advanced atrioventricular block, SSS, pacemaker implantation and sudeen cardiac death. A correlation was also made between resting heart rate and increased blood pressure and hypertension. Metagenomic Analysis: The data taken from the GWAS analysis was used to locate certain regions of genes that may have a correlation with elevations in heart rate. Proteonmic experiments analyzing protein levels in a mouse heart dealing with a B1 andrenergic receptor, eQTL anaylsis in blood, in silico search for potentially functional varaints and an automated literature search using SNIPPER were used to locate specific genes along these 21 loci with likely correlation to heart rate. 49 genes were isolated, and these genes were analyzed using 2 series of experiments using D. melanogaster ''and D. reiro. '' In stage 1, heart rate and risk of arrhythmia were used to compare wild type fruit flies to fruit flies that had the designated genes downregulated by RNAi. This was done both at rest and during a period of elevated heart rate. Stage 2 used zebrafish to compare heart rate and fractional shortening of the ventricular chamber in control embryos and embryos that had been downregulated using morpholino oligonucleotides. Results suggest that 20 of the 31 analyzed candidate genes tested across the two species play a role in heart rate regulation. Works Cited *“Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders .” Marcel den Hoed, Mark Eijgelsheim, et al. Nature Genetics 45, 621–631 (2013) doi:10.1038/ng.2610 Received 07 December 2012 *"Increase in resting heart rate is a signal worth watching." Howard LeWine MD. Harvard Health Publications. Harvard Medical School. December 21, 2011 *